The use of autogenous bone graft is the current gold standard in the 1.5 million bone-grafting surgeries performed annually in the United States. Although this practice has resulted in high rates of fusion success, it is associated with increased operative time and blood loss, along with a significant degree of donor-site morbidity. Additionally, in certain settings such as revision cases, multilevel constructs, or in patients with medical comorbidities, autogenous bone graft may exist in limited quantity and quality. This significant need for a suitable alternative to autogenous bone graft has stimulated great interest in the exploration of bone graft substitutes and extenders.
One avenue of extensive research involves the use of bone morphogenetic proteins (BMP). BMPs are osteoinductive proteins in the superfamily of transforming growth factor-beta (TGF-β). Since their discovery, several BMPs have been identified and are currently being produced in mass quantities using recombinant technologies. Recombinant human osteogenic protein-1 (rhOP-1), also known as rhBMP-7, and rhBMP-2 are the only two BMPs currently approved for orthopedic procedures. Both have shown to be effective osteoinductive proteins in preclinical and clinical trials. These growth factors provide a potential alternative to autogenous bone graft and are capable of overcoming the suboptimal biological environment for bone formation seen in revision surgeries and in patients with risk factors for psuedoarthrosis. Unfortunately, the utility of these alternatives is limited by their cost, and associated risks, such as local inflammatory reactions, ectopic bone formation, and the theoretical risks of carcinogenicity, and teratogenicity. The risk for these adverse factors increase in a dose-dependant manner and are present at the doses currently used for orthopedic procedures.
Growth factors are substances, including peptides, which affect the growth and differentiation of defined cell populations in vivo or in vitro. Normal bone formation occurs during development, bone remodeling occurs in adult life, and bone repair occurs in order to preserve the integrity of the skeleton. Bone formation, remodeling and repair involve bone resorption by osteoclasts and bone formation by osteoblasts. Cell differentiation and the activity of osteoblasts and osteoclasts are regulated by growth factors. Thus, any interference between the balance in cell differentiation and resorption can affect bone homeostasis, bone formation and repair.
The induction of ectopic bone formation by demineralized bone matrix (DBM) has been described. Further, the properties of the partially purified protein fraction, including BBP have been described. BBP is a synthetic, cyclic, 19 amino acid peptide. The sequence for this peptide is based on that of a portion of a 18.5 kD protein called “bone morphogenetic protein/noncollagenous protein” (BMP/NCP) which had no independent osteogenic activity. This protein was found to be identical to a fragment of a previously isolated protein, spp24 (secreted phosophoprotein 24 kD). Spp24 shares with other BMP binding proteins, such as fetuin, a cystatin domain which in turn contains a smaller motif, the TRH-1 (TGF-β receptor II homology 1) domain. Spp24 binds to BMP-2 and has been shown to inhibit its osteogenic activity in an ectopic bone formation model and in a transgenic model of bone formation.
Safe, effective and affordable compositions, devices and methods are desired to enhance bone formation and repair, including treatment of bone disorders (such as osteoporosis), bone injury (such as fracture healing of flat (e.g., membranous) and long (e.g., endochondral) bones, non-union fractures and reconstructive surgery), sites of knee/hip/joint repair or replacement surgery treating periodontitis, periodontal regeneration, alveolar ridge augmentation for tooth implant reconstruction, for example.